Maternally derived antibodies are crucial for protecting infants during their first months of life. This is best exemplified in infants with agammaglobulinemia, who thrive during the first year of life but succumb to repeated infections after the levels of circulating maternal antibodies wane. There is however, one downside to maternal antibodies; they suppress vaccine-induced activation of the infant immune system. Because of this, many necessary and life-saving vaccines such as measles are given at delayed times, up to a year after birth. This leaves a wide window of time during which the infant is vulnerable to infection but unable to develop the antibody response necessary for its own protection. Understanding how to activate the infant immune system in the presence of maternal antibodies is a critical area of research because it could lead to the development of more efficacious infant vaccines. We reasoned that maternal antibody-mediated suppression could in part be due to the form of the antigen used for vaccination. Our preliminary data show that immunization with soluble but not particulate antigens lead to significant activation of the infant immune system. Based upon this, our central hypothesis is that maternal antibody mediated immunosuppression of the new born immune system can be overcome and that robust long-term protective immunity can be generated by immunizing the new born with soluble rather than particulate antigens. We will test our central hypothesis by pursuing three specific aims. In Aim 1, we will fully characterize the infant immune responses induced by soluble antigens in the presence of maternal antibodies. In Aim 2, we will probe the extent of this protective immunity using H1N1, H3N2 and H5N1 influenza virus challenge models. Finally, in Aim 3, we will determine the extent to which maternal antibody mediated suppression can be overcome in non-human primate, rhesus macaque infants. The proposed work is significant because knowledge gained from these studies will enable us to develop vaccines that overcome maternal antibody suppression and can be used to successfully vaccinate infants.